Interleukin-6: An Important Mediator of Allograft Injury

Interleukin 6 (IL-6) is a cytokine with critical innate and adaptive immunity functions. It's diverse immunologic and physiologic actions include direction of immune cell differentiation, initial response to invading pathogens and ischemic injury, sustained plasma cell growth, and immunoglobulin production. IL-6 transcriptional dysregulation is commonly seen in patients with autoimmune or inflammatory disorders. Emerging information suggests IL-6 transcription is upregulated in patients with kidney and heart transplant rejection and may account for perpetuation of inflammatory responses in the allograft, leading to allograft rejection and vasculopathy. IL-6 directed therapeutics include monoclonal antibodies directed at IL-6, the IL-6 receptor (IL-6R) and Janus Kinase (JAK) inhibitors. IL-6 mediated signaling to cell targets is unique, involving classic signaling (IL-6->IL-6R) cell membrane receptors, trans signaling (IL-6->soluble IL-6R->gp130) which activates any cell, and the recently discovered IL-6/IL-6R transpresentation where antigen presenting cells (APC) synthesize and express IL-6/IL-6R complexes which are transported through the cell membrane subsequently interacting with gp130 to costimulate T-cells. Currently, there are new trials in autoimmunity and heart and kidney transplantation to determine effectiveness of inhibiting IL-6/IL-6R to ameliorate chronic allograft rejection and coronary allograft vasculopathy. Therapeutic trials aimed at prevention of ischemia/reperfusion injury (IRI) to allografts based on animal data should be considered.